Dendritic cells, autophagy and antiviral immunity.

摘要

Recognition of viral infection and initiation of host defense is controlled by multiple mechanisms in vivo. A key cell type capable of linking innate recognition to adaptive immune responses is the dendritic cell (DC). However, the relative contributions of DC subsets in naive T cell priming, and the cellular process required for viral recognition and Ag presentation by DC subsets are unclear. The goal of this thesis is to identify DC subsets responsible for initiating adaptive immune responses and to elucidate the mechanism utilized by DCs to recognize viral infection and to present Ag. First, to understand the role of DC subsets in T cell priming following virus infection at different anatomical sites, we examined the contributions of the migratory vs. lymph node-resident DC subsets to present Ag to CD4 and CD8 T cells following needle injection, epicutaneous infection or vaginal mucosal HSV-1 infection. We show that upon needle injection of HSV-1, the virus was rapidly presented by lymph node-resident DCs to CD4 and CD8 T cells, while tissue-derived migrant DCs presented Ags upon arrival in the dLNs following mucosal HSV-1 infection. These data revealed that mucosal infections are handled optimally by local DCs migrating from the site of infection to the dLNs. Second, we examined the mechanism by which pDC detect viruses within the endosome via TLR7. We observed that pDC responses to certain single-stranded RNA viruses occur only following live viral infection. We asked how cytosolic replication of viruses lead to activation of TLRs in the endosomes. The only known pathway of delivery of cytosolic material to the endosome is a process called autophagy. We demonstrated that autophagy is required for the recognition of RNA viruses that require cytosolic replication to stimulate TLR7. Finally, we examined the contribution of autophagy in Ag presentation by DCs. While cDCs defective in autophagy are capable of capturing antigens, migrating to the dLN, maturation and undergoing full cytokine secretion, they were impaired in their capacity to process and present phagocytosed Ag to CD4 T cells. The defective antigen presentation by AtgS deficient DCs was due to impaired fusion between the phagosome and the lysosome. In all, these studies contribute to our knowledge of DC biology and revealed two fundamental roles of autophagy in both innate viral recognition and antigen presentation and initiation of adaptive immunity.